The objective of this proposal is to identify internalizing cardio-specific ligands to target the delivery of therapeutic agents for the treatment of cardiovascular diseases. Gene therapy offers a novel approach for the prevention and treatment of heart disease; however, the fundamental obstacle to improving current protocols is the development of vectors that exhibit high efficacy and specificity of gene and drug delivery. While significant advances have been made towards identifying tissue-specific targeting ligands for therapeutic compounds, these ligands have been limited almost exclusively to those that bind the vasculature of organ systems and tumors. We propose to use novel phage display technology to select for internalizing ligands that trigger receptor-mediated endocytosis, a biological process critical for the delivery of therapeutic agents. The goal is to use these ligands for the targeted delivery of therapeutic agents directly to the heart. For example, the ability to target gene therapy vectors with cardio-specific ligands would have enormous commercial applications for the developing treatments for heart disease. In addition, cardio-specific ligands would be useful for identifying receptors specifically expressed in the myocardium, which can be used as valuable drug leads for future commercialization. Thus, the identification of ligands that specifically target the heart would provide new opportunities for improving current viral vectors, as well as the development of other cardio-specific vectors for the delivery of genes and other therapeutic agents for the treatment of cardiovascular diseases.